rs202217944

Positions:

chr14-91289281-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080414.4(CCDC88C):c.4265C>T(p.Ser1422Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00466 in 1,614,026 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1422S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 28 hom. )

Consequence

CCDC88C
NM_001080414.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.09

Variant links:

Genes affected

CCDC88C (HGNC:19967): (coiled-coil domain containing 88C) This gene encodes a ubiquitously expressed coiled-coil domain-containing protein that interacts with the dishevelled protein and is a negative regulator of the Wnt signalling pathway. The protein encoded by this gene has a PDZ-domain binding motif in its C-terminus with which it interacts with the dishevelled protein. Dishevelled is a scaffold protein involved in the regulation of the Wnt signaling pathway. The Wnt signaling pathway plays an important role in embryonic development, tissue maintenance, and cancer progression. Mutations in this gene cause autosomal recessive, primary non-syndromic congenital hydrocephalus; a condition characterized by excessive accumulation of cerebrospinal fluid in the ventricles of the brain. [provided by RefSeq, Jan 2013]

CCDC88C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00935939).

BP6

Variant 14-91289281-G-A is Benign according to our data. Variant chr14-91289281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-91289281-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00315 (480/152326) while in subpopulation NFE AF= 0.00488 (332/68026). AF 95% confidence interval is 0.00445. There are 1 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88C	NM_001080414.4 linkuse as main transcript	c.4265C>T	p.Ser1422Leu	missense_variant	25/30	ENST00000389857.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88C	ENST00000389857.11 linkuse as main transcript	c.4265C>T	p.Ser1422Leu	missense_variant	25/30	5	NM_001080414.4	P1	Q9P219-1
CCDC88C	ENST00000556726.5 linkuse as main transcript	c.53C>T	p.Ser18Leu	missense_variant	1/7	5
CCDC88C	ENST00000555995.1 linkuse as main transcript	n.140C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.00315

AC:

480

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00488

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00358

AC:

891

AN:

249066

Hom.:

AF XY:

0.00361

AC XY:

488

AN XY:

135134

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.00845

Gnomad NFE exome

AF:

0.00504

Gnomad OTH exome

AF:

0.00479

GnomAD4 exome

AF:

0.00482

AC:

7042

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00469

AC XY:

3413

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00145

Gnomad4 FIN exome

AF:

0.00925

Gnomad4 NFE exome

AF:

0.00553

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00315

AC:

480

AN:

152326

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00725

Gnomad4 NFE

AF:

0.00488

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00455

Hom.:

Bravo

AF:

0.00267

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00179

AC:

ESP6500EA

AF:

0.00555

AC:

ExAC

AF:

0.00326

AC:

394

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CCDC88C: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 11, 2019

- -

CCDC88C-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Benign

0.015

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.94

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.11

Sift

Uncertain

0.0050

Sift4G

Benign

0.068

Polyphen

0.90

Vest4

0.30

MVP

0.50

MPC

0.16

ClinPred

0.046

GERP RS

5.4

Varity_R

0.12

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over